Journal of Orthopaedic Translation最新文献

{"title":"Effects of crutch-assisted walking on pain, gait, and hip function in early and middle-stage osteonecrosis: a randomized trial","authors":"Jun-Ming Zhang, Yan-Bin Wu, Ya-Zhou Li, Ting-Jie Zhao, Jia-Zhou Wu, Ze-Xian Liu, Tao Qian, Biao Ma, Yun Bai, Jia-Liang You, En-Dong Luo, Xiao-Han Sun, Ai-Yuan Wang, Da-Wei Zhang, Jiang Peng","doi":"10.1016/j.jot.2026.101140","DOIUrl":"10.1016/j.jot.2026.101140","url":null,"abstract":"<div><h3>Background</h3><div>Early-to middle-stage osteonecrosis of the femoral head (ONFH) is commonly associated with pain, gait impairment, and functional limitation. Although protective weight-bearing is frequently recommended, high-quality evidence supporting standardized crutch use as a non-surgical intervention remains limited.</div></div><div><h3>Objective</h3><div>To evaluate the effects of daily crutch-assisted walking on pain, hip function, gait performance, health-related quality of life, and bone metabolic markers in patients with early-to middle-stage ONFH.</div></div><div><h3>Methods</h3><div>In this single-center randomized controlled trial, 56 patients (96 hips) with ARCO stage I–IIIA ONFH were randomly assigned to a crutch-assisted walking group (3 months of daily use) or a control group without walking aids. Both groups received standardized pharmacological treatment. Outcomes were assessed at baseline, 45 days, and 90 days. The primary outcome was pain intensity measured by the visual analog scale (VAS). Secondary outcomes included the Harris Hip Score (HHS), hip range of motion, spatiotemporal gait parameters, SF-36 scores, and serum biomarkers related to inflammation and bone metabolism. Linear mixed-effects models were applied to account for repeated measurements and bilateral hip clustering.</div></div><div><h3>Results</h3><div>At 90 days, the crutch-assisted walking group showed lower VAS scores compared with controls (adjusted mean difference −3.1, 95% CI −3.8 to −2.5; P < 0.001). Improvements were also observed in HHS, selected gait parameters, and several exploratory serum biomarkers, including osteocalcin, total procollagen type I amino-terminal propeptide, and interleukin-6. No significant between-group difference was observed in NSAID consumption. No serious adverse events were reported.</div></div><div><h3>Conclusion</h3><div>Standardised daily crutch-assisted walking may provide short-term symptomatic and functional benefits in patients with early-to middle-stage ONFH. However, given the modest sample size, relatively short follow-up duration, and exploratory nature of several secondary outcomes, these findings should be interpreted cautiously. Further studies are required to determine whether these short-term improvements translate into long-term structural or clinical benefits.</div></div><div><h3>Trial registration</h3><div>This study was registered at the Chinese Clinical Trial Registry on January 8, 2025, with registration number ChiCTR2500095502.</div></div><div><h3>The translational potential of this article</h3><div>The findings of this randomized controlled trial provide translational evidence supporting standardized crutch-assisted walking as a feasible and low-cost conservative intervention for patients with early-to middle-stage osteonecrosis of the femoral head. By demonstrating improvements in pain, gait performance, and hip function without activity restriction, this study informs everyday clinic","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101140"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13311136/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352156","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An SSK1-loaded decellularized annulus fibrosus matrix-based PD hydrogel alleviates intervertebral disc degeneration through modulation of NF-κB signaling and ferroptosis","authors":"Guantong Sun,&nbsp;Qingyu Yao,&nbsp;Xiangchen He,&nbsp;Julong Lu,&nbsp;Jianing Yu,&nbsp;Xianhao Sheng,&nbsp;Derong Xu,&nbsp;Chuanli Zhou","doi":"10.1016/j.jot.2026.101168","DOIUrl":"10.1016/j.jot.2026.101168","url":null,"abstract":"<div><h3>Background</h3><div>Intervertebral disc degeneration (IDD) is a major cause of low back pain and is closely associated with inflammatory activation, extracellular matrix (ECM) degradation, cellular senescence, and ferroptosis in nucleus pulposus cells (NPCs). In this study, we aimed to clarify the therapeutic effects and underlying mechanisms of SSK1 and to develop an injectable SSK1-loaded hydrogel for localized and sustained treatment of IDD.</div></div><div><h3>Methods</h3><div>An interleukin-1β (IL-1β)-induced NPC degeneration model was established to evaluate ECM metabolism, ferroptosis, senescence, and inflammatory signaling. Ferroptosis-related rescue experiments, pharmacological modulation of NF-κB and PPARγ, and PPARγ knockdown were performed to investigate the underlying mechanism. SSK1 was incorporated into a poly (ethylene glycol) diacrylate/decellularized annulus fibrosus matrix hydrogel (SSK1@PD). The physicochemical properties, cytocompatibility, sustained-release behavior, and therapeutic efficacy of SSK1@PD were evaluated in vitro and in a puncture-induced rat model of IDD using radiographic, histological, immunohistochemical, and biochemical analyses.</div></div><div><h3>Results</h3><div>SSK1 markedly attenuated IL-1β-induced degenerative changes in NPCs, including ECM degradation, iron accumulation, lipid peroxidation, GPX4 loss, and cellular senescence. Mechanistically, SSK1 restored PPARγ expression and suppressed NF-κB activation. PPARγ silencing largely abolished the protective effects of SSK1, whereas pharmacological activation of PPARγ partially reproduced them. The SSK1@PD hydrogel exhibited favorable physicochemical properties, good cytocompatibility, and sustained drug release. In vivo, local injection of SSK1@PD preserved disc height and histological architecture, improved ECM homeostasis, and reduced ferroptosis-, senescence-, and NF-κB-related changes in degenerated discs.</div></div><div><h3>Conclusion</h3><div>SSK1@PD alleviates IDD by enabling sustained local delivery of SSK1 and modulating degenerative cellular responses, at least in part through the PPARγ/NF-κB/ferroptosis axis. This injectable biomaterial-based platform represents a promising minimally invasive therapeutic strategy for IDD.</div></div><div><h3>The translational potential of this article</h3><div>In this study, we propose an injectable hydrogel system for localized delivery of SSK1 to treat intervertebral disc degeneration. By targeting ferroptosis and inflammation while enabling sustained drug release, this strategy effectively alleviates disc degeneration in vivo. The combination of mechanistic targeting and biomaterial-based delivery highlights its potential as a minimally invasive and clinically translatable therapy for IDD.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"59 ","pages":"Article 101168"},"PeriodicalIF":9.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13355030/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulation of the glycolysis–mitochondrial metabolism axis in osteoarthritis: mechanisms and therapeutic implications","authors":"Ren Zhang ,&nbsp;Su-Zhen Chen ,&nbsp;Shang-Chun Guo ,&nbsp;Shi-Cong Tao","doi":"10.1016/j.jot.2026.101089","DOIUrl":"10.1016/j.jot.2026.101089","url":null,"abstract":"<div><div>Osteoarthritis (OA) is a chronic degenerative joint disease affecting more than 595 million people worldwide. Progressive cartilage degeneration is closely linked to metabolic reprogramming in chondrocytes. Unlike other joint-resident cells, chondrocytes rely on a distinctive, largely glycolysis-dependent mode of glucose utilisation that must be tightly regulated to maintain cellular homeostasis. Glucose metabolism spans cytosolic glycolysis and mitochondrial oxidative phosphorylation, and growing research has clarified how each contributes to the pathophysiology of OA. Building on these advances, we synthesise current mechanistic evidence to conceptualise chondrocyte glucose metabolism as an integrated continuum, proposing the glycolysis–mitochondrial metabolism–OA axis as a unifying framework. We outline how axis disruption provides a coherent lens for understanding metabolic dysfunction in OA, and we highlight mechanistic insights with translational potential, including candidate targets that may support future diagnosis and therapy. Together, this literature review aims to sharpen the conceptual link between metabolic homeostasis and cartilage integrity, and to guide the development of mechanism-informed strategies for degenerative joint disease.</div></div><div><h3>The translational potential of this article</h3><div>This literature review outlines the mechanistic framework of a glycolysis–mitochondrial metabolism–OA axis and highlights actionable biomarkers and integrated therapeutic strategies that may guide the development of dual-target interventions for precision OA treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101089"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147858614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RhoA deficiency in chondrocyte inhibits cartilage fibrosis and ameliorates osteoarthritis progression via SOX4/MMP2 axis","authors":"Yizhou Xu ,&nbsp;Shuyi Xu ,&nbsp;Jiayi Li ,&nbsp;Shicheng Wang ,&nbsp;Jie Liang ,&nbsp;Jiaqi Wang ,&nbsp;Xianghai Wang ,&nbsp;Gang Deng ,&nbsp;Lixin Zhu ,&nbsp;Jiasong Guo","doi":"10.1016/j.jot.2026.101127","DOIUrl":"10.1016/j.jot.2026.101127","url":null,"abstract":"<div><h3>Background</h3><div>Cartilage fibrosis plays a critical role in the onset and progression of osteoarthritis (OA), and although RhoA is a well-known small GTPase that regulates cytoskeletal reorganization, its role in OA progression remains inadequately explored.</div></div><div><h3>Methods</h3><div>In this study, we first screened public scRNA-seq datasets for genes enriched in fibrocartilage chondrocytes and found that <em>RHOA</em> is significantly upregulated in fibrocartilage chondrocytes within OA cartilage obtained from patients undergoing total knee arthroplasty. Then, we induced post-traumatic OA in 8-week-old male C57BL/6J mice by destabilization of the medial meniscus and generated chondrocyte-specific <em>Rhoa</em> deletion using <em>Col2a1</em>-CreERT-<em>Rhoa</em>-flox/flox mice. After that, cartilage damage was graded by Safranin-O/Fast Green, Toluidine blue, and Micro-CT, and molecular changes were validated by Immunofluorescence and Western blot, leading to the identification—by integrated single-cell and bulk RNA-seq—of a β-catenin/SOX4/MMP2 axis downstream of RhoA. Finally, we injected AAV-<em>Sox4</em> or AAV-<em>Mmp2</em> intra-articularly to rescue the loss of RhoA function.</div></div><div><h3>Results</h3><div>The results showed that conditional knockout of <em>Rhoa</em> in chondrocytes resulted in a marked reduction in cartilage fibrosis and a concurrent decrease in extracellular matrix degradation in OA mice. Mechanistically, the integrated single-cell and bulk tissue transcriptomic analyses indicated that RhoA promotes the chondrocyte transition to a fibrotic phenotype through the novel β-catenin/SOX4/MMP2 pathway, while notably, intra-articular delivery of adeno-associated viral vectors overexpressing <em>Sox4</em> or <em>Mmp2</em> reversed the phenotypes of <em>Rhoa</em>-deficient mice.</div></div><div><h3>Conclusion</h3><div>These findings position <em>RHOA</em> as a central regulator of chondrocyte fibrosis and as a promising therapeutic target for OA treatment.</div></div><div><h3>The translational potential of this article</h3><div>These findings highlight that RhoA may represent a therapeutic target for ameliorating cartilage fibrosis and the OA process via targeted gene intervention.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101127"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel non-invasive approach monitoring skeletal stem cell function through 18F-Pentixafor PET-CT","authors":"Zan Li ,&nbsp;Dongsheng Zhang ,&nbsp;Dilibire Adili ,&nbsp;Jie Han ,&nbsp;Zhenwen Xie ,&nbsp;Qianhe Xu ,&nbsp;Lixin Tian ,&nbsp;Guangfa Wang ,&nbsp;Guolin Wang ,&nbsp;Peipei Wang ,&nbsp;Matthew B. Greenblatt ,&nbsp;Xinhui Su","doi":"10.1016/j.jot.2026.101129","DOIUrl":"10.1016/j.jot.2026.101129","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Fracture nonunion remains a major clinical challenge and is closely associated with dysfunction of osteogenic-lineage cells and their progenitors, skeletal stem cells (SSCs). However, conventional clinical approaches lack the specificity required to assess SSC functional status &lt;em&gt;in vivo&lt;/em&gt;. Radiotracer-based positron emission tomography-computed tomography (PET-CT) provides an opportunity for noninvasive functional imaging of SSCs.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;We first integrated RNA sequencing with FDA-approved radiotracers, to demonstrate &lt;em&gt;Cxcr4&lt;/em&gt; expression in murine SSCs, sorted by fluorescence-activated cell sorting (FACS), compared to non-stem skeletal cells (NSCs). Furthermore, we isolated SSCs and cultured them &lt;em&gt;in vitro&lt;/em&gt; with CXCR4-agonist or antagonist to evaluate the role of CXCR4 in SSC differentiation and mineralization. We utilized &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor, a clinically available CXCR4-targeting radiotracer, was used for &lt;em&gt;in vivo&lt;/em&gt; PET-CT imaging to monitor SSCs in both murine models and human patients. We then generate bi-cortical femoral fracture models, take advantage of three-point bending tests and combined &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor-based PET-CT to assess the correlation of &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor uptake and biomechanical tests in bone regeneration. Bone phenotype of murine models was analyzed using micro-CT and histological studies. And we finally involved a case-report of a young patient suffering hamulus fracture to evaluate the role of &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor-based PET imaging in assessing bone regeneration and assist in decision on clinical administration to approve the translational potency of &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor-based PET imaging.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;By integrating SSC RNA sequencing with FDA-approved or radiotracers in III/IV phase clinical trials, we identified CXCR4 as a promising diagnostic target and evaluated SSC activity using &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor, a clinically available CXCR4-targeting radiotracer. Bulk RNA sequencing demonstrated markedly enriched &lt;em&gt;Cxcr4&lt;/em&gt; expression in SSCs relative to non-stem skeletal cells (NSCs), a finding supported by CXCR4 co-localization with SSC markers in fracture callus and by &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor accumulation in the human growth plate. CXCR4 signaling also reflected SSC function, as CXCR4 agonist stimulation enhanced SSC differentiation and mineralization &lt;em&gt;in vitro&lt;/em&gt;, whereas antagonists impaired these processes and delayed fracture healing &lt;em&gt;in vivo&lt;/em&gt;. In mice, &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor uptake was higher in young than aged femoral metaphyses, consistent with reduced tracer uptake in the femoral heads of aged human subjects. Compared with &lt;sup&gt;18&lt;/sup&gt;F-FDG and &lt;sup&gt;18&lt;/sup&gt;F-NaF, &lt;sup&gt;18&lt;/sup&gt;F-Pentixafor more accurately predicted biomechanical properties of fracture repair. A prospective case further demonstrated clinical feasibility in monitoring hamulus healing.&lt;/di","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101129"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147995757","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The neuro–skeletal crosstalk: Mechanisms, clinical implications, and smart material interventions","authors":"Wenhui Liu ,&nbsp;Xiekai Shen ,&nbsp;Yuxiang He ,&nbsp;Zhihao Ding ,&nbsp;Jin Zhou ,&nbsp;Jingzhen Guo ,&nbsp;Xiang Lin ,&nbsp;Liangzhi Zhang ,&nbsp;Peihua Yuan ,&nbsp;Yihang Wu ,&nbsp;Jiashuo Guo ,&nbsp;Xinghao Rong ,&nbsp;Lehui Sun ,&nbsp;Enyu Yu ,&nbsp;Yuan Shi ,&nbsp;Jiye He ,&nbsp;Yun Ji ,&nbsp;Tao Li ,&nbsp;Jinwu Wang ,&nbsp;Tao Wu","doi":"10.1016/j.jot.2026.101130","DOIUrl":"10.1016/j.jot.2026.101130","url":null,"abstract":"<div><div>In recent years, the concept of neuro–skeletal crosstalk, highlighting the reciprocal interactions between the nervous and skeletal systems, has opened new avenues for understanding the pathogenesis and intervention strategies of complex diseases. This review summarizes the roles of molecular networks such as neurotransmitters, endocrine factors, immune mediators, and extracellular vesicles in bone metabolism, repair, and neurodegenerative diseases, with an emphasis on recent advances regarding bone–derived signals—including the Piezo1 channel and osteocalcin—in neural regulation. Building on this foundation, we focus on advances in frontier materials such as nanomaterials and hydrogels for modulating the brain–bone microenvironment and facilitating coordinated tissue regeneration, as well as new strategies for targeted drug delivery and immune microenvironment modulation. Empowered by next–generation technologies—including multi–omics, artificial intelligence, and organ–on–a–chip systems—the investigation of the fundamental mechanisms and personalized interventions of the brain–bone axis is entering a new era of opportunity. We hope that this review will provide a theoretical basis and valuable reference for future mechanistic studies and innovation in this interdisciplinary field.</div></div><div><h3>Translational potential</h3><div>By elucidating bidirectional regulatory networks, this review underscores the significant translational potential of targeting the brain–bone axis (BBA) for the treatment of skeletal disorders and neurodegenerative comorbidities. Therapeutic strategies harnessing neurotransmitters (e.g., norepinephrine, serotonin) and neuropeptides (e.g., CGRP) can directly modulate osteoblastic/osteoclastic activity and immune responses, thereby orchestrating fracture repair and metabolic homeostasis. The integration of functional materials—such as stimuli–responsive hydrogels, nanomaterials, and bioelectronic devices—enhances the spatiotemporal precision of signal modulation and facilitates drug delivery across biological barriers, including the blood–brain barrier (BBB). However, challenges regarding low cross–organ targeting efficiency, the complexity of dynamic pathological microenvironments, and physiological discrepancies between animal models and humans necessitate further optimization. Advances in multi–omics analysis, AI–driven network modeling, and intelligent biomimetic delivery systems hold promise for bridging these gaps, offering scalable solutions for clinical translation. This work highlights neuro–skeletal modulation as a transformative dual–targeting strategy for complex diseases, yet its implementation remains contingent upon the refinement of precise intervention technologies and rigorous clinical validation.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101130"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148178198","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From local tissue repair to systemic precision orthopaedics: recent advances in musculoskeletal regeneration and translational medicine","authors":"Shunyi Lu,&nbsp;Qin Shi,&nbsp;Huilin Yang","doi":"10.1016/j.jot.2026.101153","DOIUrl":"10.1016/j.jot.2026.101153","url":null,"abstract":"","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101153"},"PeriodicalIF":9.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308506/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345458","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tristetraprolin protects against osteoarthritis by restraining chondrocyte mitochondrial DNA release through post-transcriptional regulation","authors":"Hong Huang,&nbsp;Jianmao Chen,&nbsp;Yingshi Zhan,&nbsp;Song Xue,&nbsp;Pengcheng Hu,&nbsp;Mingze Tang,&nbsp;Shiqian Huang,&nbsp;Yang Zhao,&nbsp;Cuixi Wu,&nbsp;Muhui Zeng,&nbsp;Hao Yang,&nbsp;Ze Chen,&nbsp;Zhaohua Zhu,&nbsp;Wende Xiao,&nbsp;Weiyu Han,&nbsp;Changhai Ding,&nbsp;Yan Zhang,&nbsp;Guangfeng Ruan","doi":"10.1016/j.jot.2026.101105","DOIUrl":"10.1016/j.jot.2026.101105","url":null,"abstract":"<div><h3>Background and objective</h3><div>Osteoarthritis (OA) is a degenerative joint disease characterized by cartilage degradation and chronic inflammation. Tristetraprolin (TTP) is an RNA-binding protein with anti-inflammatory properties, but its role in OA remains unclear. This study aimed to investigate the function of TTP in chondrocytes and elucidate its mechanism in protecting against OA.</div></div><div><h3>Methods</h3><div>TTP expression was assessed in human OA cartilage and IL-1β-treated chondrocytes using immunohistochemistry and western blotting. Functional studies were performed in primary chondrocytes and cartilage explants using siRNA-mediated knockdown or plasmid-mediated overexpression of TTP. In vivo, chondrocyte-specific TTP knockout and overexpression models were established in mice. RNA-sequencing, RNA immunoprecipitation, mRNA decay assays, and luciferase reporter assays were performed to identify and validate TTP targets. The role of the identified target, CMPK2, and its downstream cGAS/STING/NF-κB pathway was investigated both in vitro and in vivo. Finally, the therapeutic potential of arctigenin, a TTP-activating natural compound, was evaluated in OA model mice.</div></div><div><h3>Results</h3><div>TTP expression was significantly downregulated in OA cartilage. TTP deficiency exacerbated OA pathology, while its overexpression protected against cartilage degeneration. Mechanistically, TTP was found to bind directly to the 3′-UTR of CMPK2 mRNA, promoting its degradation. This, in turn, reduced the release of mtDNA into the chondrocyte cytoplasm and suppressed the activation of the cGAS/STING/NF-κB signaling pathway. Furthermore, arctigenin, a natural compound from <em>Arctium lappa</em>, was identified as a TTP-dependent pharmacological activator that suppressed CMPK2 expression and mitigated OA progression in vivo.</div></div><div><h3>Conclusion</h3><div>TTP protects chondrocytes against OA by restraining CMPK2-mediated mtDNA cytoplasm release and suppressing cGAS/STING/NF-κB signaling. Arctigenin exerts its chondroprotective effects in a TTP-dependent manner and represents a promising therapeutic candidate for OA.</div></div><div><h3>The translational potential of this article</h3><div>This study identifies a novel TTP–CMPK2–mtDNA–cGAS/STING/NF-κB signaling axis in chondrocytes, revealing a mechanistic pathway that contributes to OA pathogenesis. By demonstrating that arctigenin can activate TTP to suppress cartilage degeneration, these findings highlight a potential therapeutic strategy for OA. Targeting post-transcriptional regulation via TTP may inform the development of novel disease-modifying interventions, supporting translational applications in OA treatment.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101105"},"PeriodicalIF":9.8,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13308511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148345510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut-bone axis crosstalk: Microbiota-driven immune-metabolic-neural networks in bone disorders and precision interventions","authors":"Rong Qin ,&nbsp;Peng Yu ,&nbsp;Hui Wang ,&nbsp;Jing Zhou ,&nbsp;Rui Gong ,&nbsp;Yiyao Duan ,&nbsp;Hongping Jia ,&nbsp;Mingzhu Xie ,&nbsp;Yucheng Zhou ,&nbsp;Jun Hu","doi":"10.1016/j.jot.2026.101126","DOIUrl":"10.1016/j.jot.2026.101126","url":null,"abstract":"<div><div>The gut microbiota regulates bone metabolism via a complex gut-bone axis involving short-chain fatty acids (SCFAs), immune modulation, and neuroendocrine signals. However, the precise mechanisms remain unclear, and microbiota-targeted interventions (probiotics, prebiotics, fecal microbiota transplantation) are not yet optimized for clinical use. This review systematically synthesizes the immune-metabolic-neural interaction network within the gut-bone axis, highlighting non-linear crosstalk among SCFAs, bile acids, tryptophan derivatives, immune cells (macrophages, Treg/Th17), and vagus nerve signaling. We critically assess translational hurdles, including heterogeneous study designs, confounding factors, and lack of causal evidence. Based on this network perspective, we propose a framework for future research that prioritizes multi-omics approaches, stratified interventions, and rigorous trials. This synthesis advances understanding of how gut dysbiosis drives bone disorders and paves the way for precision skeletal medicine.</div></div><div><h3>Translational potential statement</h3><div>This review identifies microbial markers for risk stratification of bone metabolic disorders and discusses SCFA-based strategies and fecal microbiota transplantation (FMT) in conditions including osteoporosis, impaired fracture healing, rheumatoid arthritis, and glucocorticoid-associated osteonecrosis. It provides testable hypotheses for large-scale randomized controlled trials (RCTs), directly supporting translation of microbiome research into clinical practice for bone disorders.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101126"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitination in intervertebral disc degeneration: from mechanisms to potential therapeutic strategies","authors":"Xuening Liu ,&nbsp;Xuewen Kang","doi":"10.1016/j.jot.2026.101124","DOIUrl":"10.1016/j.jot.2026.101124","url":null,"abstract":"<div><div>Intervertebral disc degeneration (IDD) is the primary cause of low back pain, imposing a heavy economic burden on individuals and society. The pathogenesis of IDD involves complex pathological processes. The interaction of extracellular matrix metabolism, regulated cell death (such as apoptosis, ferroptosis, pyroptosis, and autophagy), cell senescence, oxidative stress, and inflammatory response collectively contribute to the development of IDD. As a widespread post-translational modification, ubiquitination modulates various biological processes by regulating the activity and stability of proteins, including cell signal transduction, cell metabolism, and cell cycle. Recent studies have shown that ubiquitination plays an important role in the pathological process of IDD. This review systematically elucidates the molecular mechanisms by which ubiquitination regulates the progression of IDD. In addition, we summarize ubiquitination-based therapeutic strategies, including natural molecules, small-molecule compounds, extracellular vesicles, and bioactive materials. This review provides new insights and potential targets for understanding the molecular mechanisms of IDD as well as the treatment.</div><div>The translational potential of this article: This study systematically clarifies the regulatory network of ubiquitination in IDD and identifies specific E3 ligases and DUBs as potential targets. Furthermore, we critically evaluate the advantages and challenges of ubiquitination-based therapeutic strategies, providing novel insights with both mechanistic depth and broad application prospects for breaking through the bottlenecks in the clinical treatment of IDD.</div></div>","PeriodicalId":16636,"journal":{"name":"Journal of Orthopaedic Translation","volume":"58 ","pages":"Article 101124"},"PeriodicalIF":5.9,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147951593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}